Nature structural & molecular biology最新文献_第6页

A roadmap for ribosome assembly in human mitochondria 人类线粒体核糖体组装路线图

Nature structural & molecular biology Pub Date : 2024-07-11 DOI: 10.1038/s41594-024-01356-w

Elena Lavdovskaia, Elisa Hanitsch, Andreas Linden, Martin Pašen, Venkatapathi Challa, Yehor Horokhovskyi, Hanna P. Roetschke, Franziska Nadler, Luisa Welp, Emely Steube, Marleen Heinrichs, Mandy Mong-Quyen Mai, Henning Urlaub, Juliane Liepe, Ricarda Richter-Dennerlein

{"title":"A roadmap for ribosome assembly in human mitochondria","authors":"Elena Lavdovskaia, Elisa Hanitsch, Andreas Linden, Martin Pašen, Venkatapathi Challa, Yehor Horokhovskyi, Hanna P. Roetschke, Franziska Nadler, Luisa Welp, Emely Steube, Marleen Heinrichs, Mandy Mong-Quyen Mai, Henning Urlaub, Juliane Liepe, Ricarda Richter-Dennerlein","doi":"10.1038/s41594-024-01356-w","DOIUrl":"https://doi.org/10.1038/s41594-024-01356-w","url":null,"abstract":"Mitochondria contain dedicated ribosomes (mitoribosomes), which synthesize the mitochondrial-encoded core components of the oxidative phosphorylation complexes. The RNA and protein components of mitoribosomes are encoded on two different genomes (mitochondrial and nuclear) and are assembled into functional complexes with the help of dedicated factors inside the organelle. Defects in mitoribosome biogenesis are associated with severe human diseases, yet the molecular pathway of mitoribosome assembly remains poorly understood. Here, we applied a multidisciplinary approach combining biochemical isolation and analysis of native mitoribosomal assembly complexes with quantitative mass spectrometry and mathematical modeling to reconstitute the entire assembly pathway of the human mitoribosome. We show that, in contrast to its bacterial and cytosolic counterparts, human mitoribosome biogenesis involves the formation of ribosomal protein-only modules, which then assemble on the appropriate ribosomal RNA moiety in a coordinated fashion. The presence of excess protein-only modules primed for assembly rationalizes how mitochondria cope with the challenge of forming a protein-rich ribonucleoprotein complex of dual genetic origin. This study provides a comprehensive roadmap of mitoribosome biogenesis, from very early to late maturation steps, and highlights the evolutionary divergence from its bacterial ancestor.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141584474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Resolving chaperone-assisted protein folding on the ribosome at the peptide level 在肽水平上解决核糖体上的伴侣辅助蛋白质折叠问题

Nature structural & molecular biology Pub Date : 2024-07-10 DOI: 10.1038/s41594-024-01355-x

Thomas E. Wales, Aleksandra Pajak, Alžběta Roeselová, Santosh Shivakumaraswamy, Steven Howell, Svend Kjær, F. Ulrich Hartl, John R. Engen, David Balchin

{"title":"Resolving chaperone-assisted protein folding on the ribosome at the peptide level","authors":"Thomas E. Wales, Aleksandra Pajak, Alžběta Roeselová, Santosh Shivakumaraswamy, Steven Howell, Svend Kjær, F. Ulrich Hartl, John R. Engen, David Balchin","doi":"10.1038/s41594-024-01355-x","DOIUrl":"https://doi.org/10.1038/s41594-024-01355-x","url":null,"abstract":"Protein folding in vivo begins during synthesis on the ribosome and is modulated by molecular chaperones that engage the nascent polypeptide. How these features of protein biogenesis influence the maturation pathway of nascent proteins is incompletely understood. Here, we use hydrogen–deuterium exchange mass spectrometry to define, at peptide resolution, the cotranslational chaperone-assisted folding pathway of Escherichia coli dihydrofolate reductase. The nascent polypeptide folds along an unanticipated pathway through structured intermediates not populated during refolding from denaturant. Association with the ribosome allows these intermediates to form, as otherwise destabilizing carboxy-terminal sequences remain confined in the ribosome exit tunnel. Trigger factor binds partially folded states without disrupting their structure, and the nascent chain is poised to complete folding immediately upon emergence of the C terminus from the exit tunnel. By mapping interactions between the nascent chain and ribosomal proteins, we trace the path of the emerging polypeptide during synthesis. Our work reveals new mechanisms by which cellular factors shape the conformational search for the native state.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141577168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

VCP/p97-associated proteins are binders and debranching enzymes of K48–K63-branched ubiquitin chains VCP/p97 相关蛋白是 K48-K63 支链泛素链的结合剂和去支链酶

Nature structural & molecular biology Pub Date : 2024-07-08 DOI: 10.1038/s41594-024-01354-y

Sven M. Lange, Matthew R. McFarland, Frederic Lamoliatte, Thomas Carroll, Logesvaran Krshnan, Anna Pérez-Ràfols, Dominika Kwasna, Linnan Shen, Iona Wallace, Isobel Cole, Lee A. Armstrong, Axel Knebel, Clare Johnson, Virginia De Cesare, Yogesh Kulathu

{"title":"VCP/p97-associated proteins are binders and debranching enzymes of K48–K63-branched ubiquitin chains","authors":"Sven M. Lange, Matthew R. McFarland, Frederic Lamoliatte, Thomas Carroll, Logesvaran Krshnan, Anna Pérez-Ràfols, Dominika Kwasna, Linnan Shen, Iona Wallace, Isobel Cole, Lee A. Armstrong, Axel Knebel, Clare Johnson, Virginia De Cesare, Yogesh Kulathu","doi":"10.1038/s41594-024-01354-y","DOIUrl":"https://doi.org/10.1038/s41594-024-01354-y","url":null,"abstract":"Branched ubiquitin (Ub) chains constitute a sizable fraction of Ub polymers in human cells. Despite their abundance, our understanding of branched Ub function in cell signaling has been stunted by the absence of accessible methods and tools. Here we identify cellular branched-chain-specific binding proteins and devise approaches to probe K48–K63-branched Ub function. We establish a method to monitor cleavage of linkages within complex Ub chains and unveil ATXN3 and MINDY as debranching enzymes. We engineer a K48–K63 branch-specific nanobody and reveal the molecular basis of its specificity in crystal structures of nanobody-branched Ub chain complexes. Using this nanobody, we detect increased K48–K63-Ub branching following valosin-containing protein (VCP)/p97 inhibition and after DNA damage. Together with our discovery that multiple VCP/p97-associated proteins bind to or debranch K48–K63-linked Ub, these results suggest a function for K48–K63-branched chains in VCP/p97-related processes.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141556737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Asymmetric apical domain states of mitochondrial Hsp60 coordinate substrate engagement and chaperonin assembly 线粒体 Hsp60 的非对称顶端结构域状态协调底物啮合和伴侣蛋白组装

Nature structural & molecular biology Pub Date : 2024-07-01 DOI: 10.1038/s41594-024-01352-0

Julian R. Braxton, Hao Shao, Eric Tse, Jason E. Gestwicki, Daniel R. Southworth

{"title":"Asymmetric apical domain states of mitochondrial Hsp60 coordinate substrate engagement and chaperonin assembly","authors":"Julian R. Braxton, Hao Shao, Eric Tse, Jason E. Gestwicki, Daniel R. Southworth","doi":"10.1038/s41594-024-01352-0","DOIUrl":"https://doi.org/10.1038/s41594-024-01352-0","url":null,"abstract":"The mitochondrial chaperonin, mitochondrial heat shock protein 60 (mtHsp60), promotes the folding of newly imported and transiently misfolded proteins in the mitochondrial matrix, assisted by its co-chaperone mtHsp10. Despite its essential role in mitochondrial proteostasis, structural insights into how this chaperonin progresses through its ATP-dependent client folding cycle are not clear. Here, we determined cryo-EM structures of a hyperstable disease-associated human mtHsp60 mutant, V72I. Client density is identified in three distinct states, revealing interactions with the mtHsp60 apical domains and C termini that coordinate client positioning in the folding chamber. We further identify an asymmetric arrangement of the apical domains in the ATP state, in which an alternating up/down configuration positions interaction surfaces for simultaneous recruitment of mtHsp10 and client retention. Client is then fully encapsulated in mtHsp60–10, revealing prominent contacts at two discrete sites that potentially support maturation. These results identify distinct roles for the apical domains in coordinating client capture and progression through the chaperone cycle, supporting a conserved mechanism of group I chaperonin function.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"61 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structures of synaptic vesicle protein 2A and 2B bound to anticonvulsants 与抗惊厥药结合的突触小泡蛋白 2A 和 2B 的结构

Nature structural & molecular biology Pub Date : 2024-06-19 DOI: 10.1038/s41594-024-01335-1

Anshumali Mittal, Matthew F. Martin, Elena J. Levin, Christopher Adams, Meng Yang, Laurent Provins, Adrian Hall, Martin Procter, Marie Ledecq, Alexander Hillisch, Christian Wolff, Michel Gillard, Peter S. Horanyi, Jonathan A. Coleman

{"title":"Structures of synaptic vesicle protein 2A and 2B bound to anticonvulsants","authors":"Anshumali Mittal, Matthew F. Martin, Elena J. Levin, Christopher Adams, Meng Yang, Laurent Provins, Adrian Hall, Martin Procter, Marie Ledecq, Alexander Hillisch, Christian Wolff, Michel Gillard, Peter S. Horanyi, Jonathan A. Coleman","doi":"10.1038/s41594-024-01335-1","DOIUrl":"https://doi.org/10.1038/s41594-024-01335-1","url":null,"abstract":"Epilepsy is a common neurological disorder characterized by abnormal activity of neuronal networks, leading to seizures. The racetam class of anti-seizure medications bind specifically to a membrane protein found in the synaptic vesicles of neurons called synaptic vesicle protein 2 (SV2) A (SV2A). SV2A belongs to an orphan subfamily of the solute carrier 22 organic ion transporter family that also includes SV2B and SV2C. The molecular basis for how anti-seizure medications act on SV2s remains unknown. Here we report cryo-electron microscopy structures of SV2A and SV2B captured in a luminal-occluded conformation complexed with anticonvulsant ligands. The conformation bound by anticonvulsants resembles an inhibited transporter with closed luminal and intracellular gates. Anticonvulsants bind to a highly conserved central site in SV2s. These structures provide blueprints for future drug design and will facilitate future investigations into the biological function of SV2s.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141425279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Epitranscriptome regulation. 上皮转录组调控。

Nature structural & molecular biology Pub Date : 2018-09-28 DOI: 10.1038/s41594-018-0140-7

Dan Dominissini, Gideon Rechavi

引用次数: 0

Intersubunit capture of regulatory segments is a component of cooperative CaMKII activation. 调控片段的亚基间捕获是CaMKII协同激活的一个组成部分。

Nature structural & molecular biology Pub Date : 2010-03-01 DOI: 10.1038/nsmb.1751

Luke H Chao, Patricia Pellicena, Sebastian Deindl, Lauren A Barclay, Howard Schulman, John Kuriyan

引用次数: 115

Domain structure of separase and its binding to securin as determined by EM. 分离酶的结构域结构及其与securin的结合。

Nature structural & molecular biology Pub Date : 2005-06-01 Epub Date: 2005-05-08 DOI: 10.1038/nsmb935

Hector Viadiu, Olaf Stemmann, Marc W Kirschner, Thomas Walz

引用次数: 51